Human umbilical cord mesenchymal stem cell-derived exosomal miR-335-5p attenuates the inflammation and tubular epithelial–myofibroblast transdifferentiation of renal tubular epithelial cells by reducing ADAM19 protein levels

Abstract

Background Renal tubular epithelial–myofibroblast transdifferentiation (EMT) plays a key role in the regulation of renal fibrosis. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) play a crucial role in alleviating renal fibrosis and injury. Additionally, hucMSC-derived exosomes contain numerous microRNAs (miRNAs). However, it is unclear whether mesenchymal stem cells can regulate the transforming growth factor (TGF)-β1-induced EMT of human renal tubular epithelial cells (RTECs) through exosomal miRNAs. Method HK-2, a human RTEC line, was co-treated with TGF-β1 and hucMSC-derived exosomes. Additionally, TGF-β1-treated HK-2 cells were transfected with a miR-335-5p mimic and disintegrin and metalloproteinase domain-containing protein 19 (ADAM19)-overexpression plasmid. miR-335-5p expression and ADAM19 protein and inflammation levels were measured via quantitative reverse transcription polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays, respectively. Results TGF-β1 treatment changed the shape of HK-2 cells from a cobblestone morphology to a long spindle shape, accompanied by an increase in interleukin (IL)-6, tumor necrosis factor-α, IL-1β, collagen I, collagen III, α-smooth muscle actin, vimentin, and N-cadherin protein levels, whereas E-cadherin protein levels were reduced in these HK-2 cells, suggesting that TGF-β1 treatment induced the inflammation and EMT of HK-2 cells. HucMSC-exosomes improved the inflammation and EMT phenotype of TGF-β1-induced HK-2 cells by transferring miR-335-5p. miR-335-5p was found to bind the ADAM19 3′-untranslated region to reduce ADAM19 protein levels. Additionally, miR-335-5p improved the inflammation and EMT phenotype of HK-2 cells by reducing ADAM19 protein levels with TGF-β1 induction. Conclusions HucMSC-derived exosomal miR-335-5p attenuates the inflammation and EMT of HK-2 cells by reducing ADAM19 protein levels upon TGF-β1 induction. This study provides a potential therapeutic strategy and identifies targets for clinically treating renal fibrosis.

Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-β-SMAD2/3 pathway

“…According to published literature, the potential modulatory effect on MFB is more likely to rely on the secretion of a spectrum of MSC-derived soluble factors and subsequent downstream signal transductions within MFB. These identified soluble factors vary to a great extent across studies, including condition medium (Filidou et al 2022 ; Zhang et al 2015 ), exosomes (Hu et al 2020 ) and a spectrum of microRNA (Qiu et al 2022 ; Basalova et al 2020 ; Fang et al 2016 ) (Additional file 1 : Table S3). By constructing in vivo and in vitro models simulating fibrotic disease, these MSC-derived factors have been revealed to block/reverse MFB differentiation and/or alleviate fibrotic phenotypes in animal models.…”

Umbilical Cord Mesenchymal-Stem-Cell-Derived Exosomes Exhibit Anti-Oxidant and Antiviral Effects as Cell-Free Therapies

“…As one of the critical stem cell derivatives, ucMSC-EXO contain a variety of growth factors, cytokines, and RNA that improve cell function and could be used as an effective cell-free therapy in many diseases [ 24 , 25 , 26 , 27 ]. Here, we further investigated the therapeutic effect of ucMSC-EXO on the H 2 O 2 -induced oxidative damage of HSFs.…”

Bladder Cancer in Exosomal Perspective: Unraveling New Regulatory Mechanisms

“…45 Moreover, exosome proteases, such as metalloproteinases, can degrade the extracellular matrix, facilitating tumor cells in breaching tissue barriers and promoting invasion. 46,47…”